The southeastern United States has experienced severe, recurrent drought, rapid human population growth, and increasing agricultural irrigation during recent decades, resulting in greater demand for the water resources. During the same time period, freshwater mussels (Unioniformes) in the region have experienced substantial population declines. Consequently, there is growing interest in determining how mussel population declines are related to activities associated with water resource development. Determining the causes of mussel population declines requires, in part, an understanding of the factors influencing mussel population dynamics. We developed Pradel reverse-time, tag-recapture models to estimate survival, recruitment, and population growth rates for three federally endangered mussel species in the Apalachicola–Chattahoochee–Flint River Basin, Georgia. The models were parameterized using mussel tag-recapture data collected over five consecutive years from Sawhatchee Creek, located in southwestern Georgia. Model estimates indicated that mussel survival was strongly and negatively related to high flows during the summer, whereas recruitment was strongly and positively related to flows during the spring and summer. Using these models, we simulated mussel population dynamics under historic (1940–1969) and current (1980–2008) flow regimes and under increasing levels of water use to evaluate the relative effectiveness of alternative minimum flow regulations. The simulations indicated that the probability of simulated mussel population extinction was at least 8 times greater under current hydrologic regimes. In addition, simulations of mussel extinction under varying levels of water use indicated that the relative risk of extinction increased with increased water use across a range of minimum flow regulations. The simulation results also indicated that our estimates of the effects of water use on mussel extinction were influenced by the assumptions about the dynamics of the system, highlighting the need for further study of mussel population dynamics.